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【结 构 式】

【药物名称】Cefixime, FK-027, CL-284635, FR-17027, Suprax, Oroken, Denvar, Necopen, Tricef, Cephoral, Suprax, Cefspan

【化学名称】(6R,7R)-7-[2-(2-Amino-4-thiazolyl)glyoxylamido]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 7(2)-(Z)-[O-(carboxymethyl)oxime]
　　　　　　7beta-[2-(2-Aminothiazol-4-yl)-2(Z)-(carboxymethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid

【CA登记号】79350-37-1

【 分 子 式 】C16H15N5O7S2

【 分 子 量 】453.45525

【开发单位】Aventis Pharma (Not Determined), Fujisawa (Not Determined), Wyeth Pharmaceuticals (Not Determined), AstraZeneca (Licensee), Esteve (Licensee), Lupin (Licensee), Merck KGaA (Licensee)

【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Cephalosporins

合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11

合成路线1

　

参考文献 中间体
【1】 Lopez M,Rodriguez Z,Gonzalez M,et al.Synthesis of (Z)-2-(2-formamido-4-thiazolyl)-2-(substituted alkoxyimino)acetic acids.Farmaco,2000,55:40.
【2】 Parthasaradhi Reddy B,Rathnakar Reddy K,Raji Reddy R,et al.An improved process for the preparation of ceficime:WO,Patent 2,006,103,686,2006.
【3】 程先波，胡立蓬，叶树祥，等.头孢克肟的制备方法：CN,Patent 101,319,246,2008.
【4】 潘行远.一种头孢克肟的合成方法：CN,Patent 101,016,305,2007.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 27907 Acetoacetic acid tert-butyl ester;3-Oxo-butanoic acid 1,1-dimethylethyl estertert-butyl 3-oxobutanoate 1694-31-1 C8H14O3 详情 详情
(II) 69635 (Z)-tert-butyl 2-(hydroxyimino)-3-oxobutanoate C8H13NO4 详情 详情
(III) 69636 (Z)-tert-butyl 2-((2-methoxy-2-oxoethoxy)imino)-3-oxobutanoate C11H17NO6 详情 详情
(IV) 69637 4-Chloro-2-[(2-methoxy-2-oxoethoxy)imino]-3-oxobutanoic acid；4-Chloro-2-(Z)-methoxycarbonylmethoxyimino-3-oxobutyric acid;(Z)-4-chloro-2-((2-methoxy-2-oxoethoxy)imino)-3-oxobutanoic acid 95759-10-7 C7H8ClNO6 详情 详情
(V) 69638 (Z)-2-(2-aminothiazol-4-yl)-2-((2-methoxy-2-oxoethoxy)imino)acetic acid 80544-17-8 C8H9N3O5S 详情 详情
(VI) 69639 (Z)-methyl 2-(((1-(2-aminothiazol-4-yl)-2-(benzo[d]thiazol-2-ylthio)-2-oxoethylidene)amino)oxy)acetate 246035-38-1 C15H12N4O4S3 详情 详情
(VII) 69640 (6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-((2-methoxy-2-oxoethoxy)imino)acetamido)-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C17H17N5O7S2 详情 详情
(VIII) 10257 methyl 2-chloroacetate; methyl chloroacetate 96-34-4 C3H5ClO2 详情 详情
(IX) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(X) 64882 (6R,7R)-7-amino-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 79349-82-9 C9H10N2O3S 详情 详情

合成路线2

　

参考文献 中间体
【1】 Sharma AK,Malhotra A,Raj B,et al.Cefixim preparation:DE,Patent 19,846,448,1999.
【2】 Sharma AK,Malhotra A,Raj B,et al.Preparation od orally active cephalosporin antibiotic-cefixim:DE,Patent 19,846,449,1999.
【3】 Deshpande PB,Das GK,Deshpande PN,et al.Process ofr the preparation of cefixime:US,Patent 6,800,755,2004.
【4】 Decristoforo M,Ludescher J,Sturm H.Process for the purification of a cephalosporin derivative:WO,Patent 9,951,607,1999.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 69640 (6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-((2-methoxy-2-oxoethoxy)imino)acetamido)-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C17H17N5O7S2 详情 详情

合成路线3

　

参考文献 中间体
【1】 Takaya T,Takasugi H,Masugi T,et al.7-Acylamino-3-substituted cephalosporanic acid derivatives,processes for their preparation and pharmaceutical compositions containing them:EP,Patent 29,557,1981.
【2】 Cabri W,Alpegiani M,Pozzi G,et al.A process for the preparation of cefixime via alkyl- or aryl-sulfonates:WO,Patent 2,003,040,148,2003.
【3】 Miller L,Sturm H.Amine Salts:WO,Patent 9,806,723,1998.
【4】 Ludescher J,Miller L,Sturm H,et al.Purification process:WO,Patent 9,831,685,1998.
【5】 Kameyama Y.Process for producing cephem compounds:WO,Patent 9,952,913,1999.
【6】 胡艾希，袁帅，宋又群，等.头孢克肟的合成.中国医药工业杂志，2004,35:3.
【7】 周永健，孟红，赵平，等.一种头孢克肟的制备方法：CN,Patent 1,69,134,2005.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 69641 (6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-((2-(tert-butoxy)-2-oxoethoxy)imino)acetamido)-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C20H23N5O7S2 详情 详情

合成路线4

　

参考文献 中间体
【1】 Deshpande PB,Luthra PK.Thioester derivatives of thiazolyl acetic acid and their use in the preparation of cephalosporin compounds:US,Patent 6,388,070,2002.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 69638 (Z)-2-(2-aminothiazol-4-yl)-2-((2-methoxy-2-oxoethoxy)imino)acetic acid 80544-17-8 C8H9N3O5S 详情 详情
(II) 69642 2-Phenyl-1,3,4-oxadiazole-5-thione;5-Phenyl-1,3,4-oxadiazole-2(3H)-thione;2-Phenyl-5-mercaptooxadiazole;5-Mercapto-2-phenyl-1,3,4-oxadiazole;2-Mercapto-5-phenyl-1,3,4-oxadiazole;5-phenyl-1,3,4-oxadiazole-2(3H)-thione 3004-42-0 C8H6N2OS 详情 详情
(III) 69643 (Z)-methyl 2-(((1-(2-aminothiazol-4-yl)-2-oxo-2-((5-phenyl-1,3,4-oxadiazol-2-yl)thio)ethylidene)amino)oxy)acetate C16H13N5O5S2 详情 详情
(IV) 64882 (6R,7R)-7-amino-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 79349-82-9 C9H10N2O3S 详情 详情

合成路线5

　

参考文献 中间体
【1】 Shinozaki K,Hayashi M,Kitayama M.Process for the preparation of cephem compound:WO,Patent 2,001,098,309,2001.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 64882 (6R,7R)-7-amino-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 79349-82-9 C9H10N2O3S 详情 详情
(II) 69644 1,1-bis(trimethylsilyl)urea C7H20N2OSi2 详情 详情
(III) 69645 (Z)-methyl 2-(((1-(2-aminothiazol-4-yl)-2-chloro-2-oxoethylidene)amino)oxy)acetate C8H8ClN3O4S 详情 详情
(IV) 69640 (6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-((2-methoxy-2-oxoethoxy)imino)acetamido)-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C17H17N5O7S2 详情 详情

合成路线6

　

参考文献 中间体
【1】 Shinozaki K,Hayashi M,Kitayama M.Process for the preparation of cephem compound:WO,Patent 2,001,098,309,2001.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成

合成路线7

　

参考文献 中间体
【1】 Picornell Dardes C.Process for the preparation of trihydrated cefixime:WO,Patent 9,553,753,1995.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 69646 2-(((benzyloxy)carbonyl)amino)thiazole-4-carboxylic acid C12H10N2O4S 详情 详情
(II) 24090 tert-butyl 2-(aminooxy)acetate C6H13NO3 详情 详情
(III) 69647 (Z)-2-(2-(((benzyloxy)carbonyl)amino)thiazol-4-yl)-2-((2-(tert-butoxy)-2-oxoethoxy)imino)acetic acid C19H21N3O7S 详情 详情
(IV) 69648 (6R,7R)-tert-butyl 7-amino-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C13H18N2O3S 详情 详情
(V) 69649 (6R,7R)-tert-butyl 7-((Z)-2-(2-(((benzyloxy)carbonyl)amino)thiazol-4-yl)-2-((2-(tert-butoxy)-2-oxoethoxy)imino)acetamido)-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C32H37N5O9S2 详情 详情

合成路线8

　

参考文献 中间体
【1】 Picornell Dardes C.Process for the preparation of trihydrated cefixime:WO,Patent 9,553,753,1995.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 24084 2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-[2-(formylamino)-1,3-thiazol-4-yl]acetic acid C12H15N3O6S 详情 详情
(II) 69648 (6R,7R)-tert-butyl 7-amino-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C13H18N2O3S 详情 详情
(III) 69650 (6R,7R)-tert-butyl 7-((Z)-2-((2-(tert-butoxy)-2-oxoethoxy)imino)-2-(2-formamidothiazol-4-yl)acetamido)-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C25H31N5O8S2 详情 详情
(IV) 69651 (6R,7R)-tert-butyl 7-((Z)-2-(2-aminothiazol-4-yl)-2-((2-(tert-butoxy)-2-oxoethoxy)imino)acetamido)-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C24H31N5O7S2 详情 详情

合成路线9

　

参考文献 中间体
【1】 Tyagi OD,Rane DR,Mahajan S,et al.Process for the preparation of cefixime:WO,Patent 2,006,067,806,2006.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 69652 (6R,7R)-7-((Z)-4-chloro-2-((2-methoxy-2-oxoethoxy)imino)-3-oxobutanamido)-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C16H16ClN3O8S 详情 详情

合成路线10

The reaction of 7-(5-amino-5-carboxypentanamido)-3-hydroxymethyl-3-cephem-4-carboxylic acid (I), first with benzoyl chloride in acetone-water, and then with diphenyldiazomethane, gives benzhydryl 7-[5-benzamido-5-(benzhydryloxycarbonyl)pentanamido]-3-hydroxymethyl-3-cephem-4-carboxylate (II), which by reaction with PCl5 is converted into the corresponding chloromethyl derivative (III). The reaction of (III) with triphenyl phosphine and NaI in DMF yields the phosphonium iodide (IV), which by a Wittig condensation with formaldehyde in methylene chloride affords benzhydryl-7-[5-benzamido-5-(benzhydryloxycarbonyl)pentanamido]-3-vinyl-3-cephem-4-carboxylate (V). The cleavage of (V) with PCl-pyridine in methylene chloride gives benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate (VI), which is condensed with 2-(tert-butoxycarbonylmethoxyimino)-2-(2-formamidothiazol-4-yl)acetic acid (VII) [prepared from 2-formamidothiazol-4-yl)oxoacetic acid (VIII) and tert-butyl aminooxyacetate (IX)] yielding benzhydryl 7-[2-tert-butoxycarbonylmethoxyimino)-2-(2-formamidothiazol-4-yl)acetamido-3-vinyl-3-cephem-4-carboxylate (X). The hydrolysis of (X) with HCl in methanol affords the 2-amino derivative (XI), which is finally fully deprotected by treatment with trifluoroacetic acid in anisole.

参考文献 中间体
【1】 Takaya, T.; Tagasuki, H.; Masugi, T.; Yamanaka, H.; Kawabata, K. (Fujisawa Pharmaceutical Co., Ltd.); Starting compounds for 7-acylamino-3-vinylcephalosporanic acid derivatives and processes for their preparation. EP 0030630; EP 0123024; EP 0244637; JP 6279452; US 4409214; US 4423213 .
【2】 Serradell, M.N.; Blancafort, P.; Castaner, J.; FR-17,027. Drugs Fut 1983, 8, 8, 682.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 31127 sodium (6R,7R)-7-[(5-amino-5-carboxypentanoyl)amino]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C14H18N3NaO7S 详情 详情
(II) 31128 benzhydryl (6R,7R)-7-[[6-(benzhydryloxy)-5-(benzoylamino)-6-oxohexanoyl]amino]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C47H43N3O8S 详情 详情
(III) 31129 benzhydryl (6R,7R)-7-[[6-(benzhydryloxy)-5-(benzoylamino)-6-oxohexanoyl]amino]-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C47H42ClN3O7S 详情 详情
(IV) 31130 ([(6R,7R)-7-[[6-(benzhydryloxy)-5-(benzoylamino)-6-oxohexanoyl]amino]-2-[(benzhydryloxy)carbonyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl)(triphenyl)phosphonium C65H57N3O7PS 详情 详情
(V) 31131 benzhydryl (6R,7R)-7-[[6-(benzhydryloxy)-5-(benzoylamino)-6-oxohexanoyl]amino]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C48H43N3O7S 详情 详情
(VI) 22001 benzhydryl (6R,7R)-7-amino-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C22H20N2O3S 详情 详情
(VII) 24084 2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-[2-(formylamino)-1,3-thiazol-4-yl]acetic acid C12H15N3O6S 详情 详情
(VIII) 24090 tert-butyl 2-(aminooxy)acetate C6H13NO3 详情 详情
(IX) 31132 2-[2-(formylamino)-1,3-thiazol-4-yl]-2-oxoacetic acid C6H4N2O4S 详情 详情
(X) 31133 benzhydryl (6R,7R)-7-([2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-[2-(formylamino)-1,3-thiazol-4-yl]acetyl]amino)-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C34H33N5O8S2 详情 详情
(XI) 31134 benzhydryl (6R,7R)-7-[(2-(2-amino-1,3-thiazol-4-yl)-2-[[2-(tert-butoxy)-2-oxoethoxy]imino]acetyl)amino]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C33H33N5O7S2 详情 详情

合成路线11

The reaction of 7-(5-amino-5-carboxypentanamido)-3-hydroxymethyl-3-cephem-4-carboxylic acid (I), first with benzoyl chloride in acetone-water, and then with diphenyldiazomethane, gives benzhydryl 7-[5-benzamido-5-(benzhydryloxycarbonyl)pentanamido]-3-hydroxymethyl-3-cephem-4-carboxylate (II), which by reaction with PCl5 under stronger conditions than before gives benzhydryl-7-amino-3-chloromethyl-3-cephem-4-carboxylate (XII), which is condensed with (VII) by means of POCl3 in DMF as before, yielding the chloromethyl compound (XIII). The reaction of (XIII) with triphenyiphosphine and NaI affords the phosphonium salt (XIV), which is finally submitted to a Wittig condensation with formaldehyde giving (X). The hydrolysis of (X) with HCl in methanol affords the 2-amino derivative (XI), which is finally fully deprotected by treatment with trifluoroacetic acid in anisole.

参考文献 中间体
【1】 Takaya, T.; Tagasuki, H.; Masugi, T.; Yamanaka, H.; Kawabata, K. (Fujisawa Pharmaceutical Co., Ltd.); Starting compounds for 7-acylamino-3-vinylcephalosporanic acid derivatives and processes for their preparation. EP 0030630; EP 0123024; EP 0244637; JP 6279452; US 4409214; US 4423213 .
【2】 Serradell, M.N.; Blancafort, P.; Castaner, J.; FR-17,027. Drugs Fut 1983, 8, 8, 682.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 31127 sodium (6R,7R)-7-[(5-amino-5-carboxypentanoyl)amino]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C14H18N3NaO7S 详情 详情
(II) 31128 benzhydryl (6R,7R)-7-[[6-(benzhydryloxy)-5-(benzoylamino)-6-oxohexanoyl]amino]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C47H43N3O8S 详情 详情
(VII) 24084 2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-[2-(formylamino)-1,3-thiazol-4-yl]acetic acid C12H15N3O6S 详情 详情
(X) 31133 benzhydryl (6R,7R)-7-([2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-[2-(formylamino)-1,3-thiazol-4-yl]acetyl]amino)-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C34H33N5O8S2 详情 详情
(XI) 31134 benzhydryl (6R,7R)-7-[(2-(2-amino-1,3-thiazol-4-yl)-2-[[2-(tert-butoxy)-2-oxoethoxy]imino]acetyl)amino]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C33H33N5O7S2 详情 详情
(XII) 31135 benzhydryl (6R,7R)-7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C21H19ClN2O3S 详情 详情
(XIII) 31136 benzhydryl (6R,7R)-7-([2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-[2-(formylamino)-1,3-thiazol-4-yl]acetyl]amino)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C33H32ClN5O8S2 详情 详情
(XIV) 31137 [[(6R,7R)-2-[(benzhydryloxy)carbonyl]-7-([2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-[2-(formylamino)-1,3-thiazol-4-yl]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl](triphenyl)phosphonium C51H47N5O8PS2 详情 详情
Extended Information